Instructing the limb for life-long health

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Whilst there is near-universal cognisance that mechanic force is a signal that cells and tissues cannot avoid, how cells, and particularly tissues, integrate mechanical cues into their developmental and homeostatic programs, is far from understood. Our group explores how cells use primary cilia, nanoscale, singular organelles, to instruct decision-making in complex biophysicochemical environments. We are particularly focussed on the musculoskeletal system, where cilia are proposed to be a nexus for a plethora of cell signalling, including mechanotransduction, but their role beyond development is largely unknown.

By deleting a core ciliary gene in vivo, we are able to demonstrate the cilium maintains critical influence in the post-natal limb. In articular cartilage it acts as a homeostatic gatekeeper; a healthy brake on pathways such as hedgehog signalling, supporting the maturation and integrity of articular cartilage. The loss of this guardian in early adulthood results in progressive tissue atrophy, predisposing cartilage in regions experiencing the highest mechanical loads, to osteoarthritis.

In the cartilaginous growth plate (GP), the template for bone elongation, loss of cilia just before the natural cessation of growth, abruptly halts GP dynamics, decoupling bone formation from chondrocyte differentiation. The GP is elongated in the regions of the growth plate that experience the highest mechanical stresses, leaving areas full of trapped hypertrophic chondrocytes, unable to transdifferentiate, whilst central regions appear unaffected. Paradoxically to the dogma that cilia might be positive regulators of mechanotransduction, we find limb immobilisation rescues normal GP dynamics. Coordinated mineralisation, mechano-regulated recruitment of osteoclasts to the epiphyseal frontier, cartilage resorption and bone invasion are all restored, suggesting the exquisitely mechanosensitive GP uses cilia to endow a degree of cellular indifference, to protect against the bombardment of mechanical cues, otherwise disruptive to this pivotal period for limb health. 2 weeks of wheel exercise acutely disrupts the coordinated ossification of the growth plate in control mice, highlighting how little we know about the adolescent MSK system, as it prepares for a life-time of locomotion.

Collectively, we propose these data indicate the discovery of a cell ‘mechanodampener’, an intrinsic part of the complex mechano-regulatory system cartilage uses to bi-directionally respond to an ever-changing mechanical environment, analogous to the bone mechanostat. This lends support to the hypothesis that cilia regulate the response to mechanics in vivo but, in cartilage at least, not in the way the original theories proposed.